Archive for March, 2014

Teams with University of Minnesota researchers to better understand workings of HIV drugs

Drugs used to treat HIV penetrate poorly into lymphatic tissues where most HIV replication takes place, and there is persistent low-level virus replication in these tissues according to research from the University of Minnesota and University of Nebraska Medical Center.

The results appear in the latest issue of the Proceedings of the National Academy of Sciences (PNAS).

“We know the drugs we use today are effective because HIV-infected persons are doing better and living longer, but these drugs cannot cure the infection,” said Courtney Fletcher, Pharm.D., the first author of the PNAS paper and dean of the College of Pharmacy at the University of Nebraska Medical Center. “We wanted to know why and thought that maybe the drugs were not getting into the tissues where most virus replication is happening.”

Dr. Fletcher joined a team with Timothy Schacker, M.D., director of the Program in HIV Medicine at the University of Minnesota and Ashley Haase, M.D., Regents’ Professor and Head of Microbiology at the University of Minnesota, to measure drug levels and find the impact on HIV-1 replication in those tissues.

“These are very complex questions requiring expertise from many disciplines to get the data required to understand what is going on,” Dr. Schacker said. “This is a great example of the kind of team science we need to make progress in curing this disease.”

Dr. Schacker, the principal investigator of the project, assembled a cohort of patients and started them on antiretroviral therapy. He collected lymph nodes and gut samples from these patients at frequent intervals.

Dr. Fletcher used highly specialized and sensitive methods, developed in his laboratory, for measuring drug levels inside cells obtained from lymph nodes and gut tissues.

“The common approach of looking at drug concentrations in plasma may provide misleading information,” Dr. Fletcher said. “What is most important to understand is the concentration of a drug actually inside an HIV-infected cell in the compartments where most of the virus is actually produced.

“What we found, in studies conducted during six months of therapy in 12 HIV-infected persons receiving combinations of five of the most commonly used drugs to treat HIV infection was that concentrations inside the cells from lymph tissues were surprisingly low compared with blood.”

Dr. Haase then used sensitive methods to precisely measure the amount and location of virus in the lymph node and gut tissues and found the virus continued to replicate in the tissues, even when it was undetectable in blood.

“Most HIV replicates in the lymph and gut tissues and that’s where we need to look to understand the efficacy of these drugs,” Dr. Haase said. “The ongoing replication we found in the lymph and gut tissues we tested directly correlated with the drug levels found there.

“This persistent low-level replication may be one cause of the chronic immune activation we find in these patients, and is likely an important factor in accelerated aging, increased cardiovascular events and early mortality common in these patients.”

Drs. Schacker, Fletcher, Haase and their collaborators are now working on a comprehensive survey of all available anti-retroviral drugs in an effort to identify a combination of drugs that will provide maximum penetration into lymph nodes and more effectively stop virus replication.

“We will not cure this disease until we can completely suppress virus replication,” Dr. Schacker said.

Funding for this research project was provided in part by the National Institutes of Health grants AI074340 and AI028433.

The College of Pharmacy at the University of Nebraska Medical Center is one of the nation’s outstanding institutions for pharmacy education and research, with its graduates advancing drug discovery, delivery and therapeutics and influencing the quality of health care in communities across Nebraska and the U.S. Visit www.unmc.edu/pharmacy to learn more.

The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school’s 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Visit www.med.umn.edu to learn more.

Through world-class research and patient care, UNMC generates breakthroughs that make life better for people throughout Nebraska and beyond. Its education programs train more health professionals than any other institution in the state. Learn more at unmc.edu and follow us on social media.

Omaha, NE– What is the impact of tobacco marketing on smokers? Researchers at the University of Nebraska Medical Center (UNMC) and Roswell Park Cancer Institute (RPCI) are asking that and other questions in a study which will examine point-of-sale tobacco advertising and smoking habits.

The three-year, $1.4 million study is being funded by the National Cancer Institute, which is part of the National Institutes of Health.

“There is a gap in our knowledge about how tobacco marketing in stores affects smoking cessation and our study will help fill this void,” said Mohammad Siahpush, Ph.D., professor at the UNMC College of Public Health. “Our goal is to examine how variations in tobacco marketing in stores influence attempts and success in stopping smoking.”

The tobacco industry spends $12.5 billion a year on marketing in the United States. As avenues for traditional tobacco marketing such as electronic, billboard, and print forms are restricted, the industry has come to rely on marketing at retail stores to advertise and promote their tobacco products. This study will help to inform health care professionals about how exposure to tobacco marketing inhibits smoking cessation.

Researchers are seeking approximately 1,000 smokers who are 18 years of age and older, have smoked more than 100 cigarettes in their life, currently smoke five or more cigarettes per day and live in the City of Omaha. Smokers will be asked to respond to a 30-minute telephone survey and, in six months, a 15-20 minute follow-up telephone survey. Eligible participants will receive a compensation for their time.

Information will be collected from each participant on a variety of smoking topics, such as their cravings to smoke, urge to buy cigarettes, unplanned purchases of cigarettes, the perception of social acceptability of smoking, and about how much they notice tobacco marketing,. Interviews will be conducted by the Survey Research and Data Acquisition Resource (SRDAR) at Roswell Park Cancer Institute in Buffalo, N.Y.

Data also will be gathered about tobacco marketing from stores that sell tobacco in each participant’s neighborhood. This study is believed to be the first smoking cessation study to use geographical information technology to link tobacco marketing data from retail stores to information collected from smokers.

“The information obtained from this study will contribute to a greater understanding of the factors that impact smoking behavior,” said Andrew Hyland, Ph.D., chair of the Department of Health Behavior at RPCI. “The study results can guide health care professionals as they consider policies that support tobacco cessation and will ultimately help smokers quit.”

For more information or to participate in the study, interested parties can call the toll-free number for the project: 1-855-600-6960.

The mission of Roswell Park Cancer Institute (RPCI) is to understand, prevent and cure cancer. Founded in 1898, RPCI is one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or email askrpci@roswellpark.org. Follow Roswell Park on Facebook and Twitter.

Through world-class research and patient care, UNMC generates breakthroughs that make life better for people throughout Nebraska and beyond. Its education programs train more health professionals than any other institution in the state. Learn more at unmc.edu and follow us on social media.

Parents today may outlive their children, according to the Robert Wood Johnson Foundation.

We are raising the first generation of youth who will live sicker and shorter lives than their parents, according to the Robert Wood Johnson Foundation. The global pediatric obesity epidemic is a primary example of why this may be true. Credible research steers us toward solutions on this one. Here’s a sampling of what the world, and Nebraska, are learning about preventing pediatric obesity.

China. Chinese researchers believe that economic expansion and exposure to western influences has led to their upsurge in pediatric obesity, associated with an increase in juvenile type 2 diabetes which has doubled within five years. Little research has been done to assess the population’s health status, and a call is made for more health screenings and lifestyle interventions.

Sweden. More than 200 families are enrolled in a study to determine the earliest changes in children that may be related to obesity. The study uniquely includes a cohort of children who are severely obese compared to a cohort of children who are lean. They are followed with health screenings including body measurements; surveys of diet, exercise and other behaviors; and blood tests measuring various hormones, growth factors, and genetics. The study began in 2010 (with likely 100 more families to be enrolled this year), and the research is already helping determine predictors of childhood diabetes related to obesity.

Central Illinois. It’s no surprise that a home that is secure and without distress leads to improved childhood eating practices rather than emotional eating. Secure parents play an important role as they are flexible in expressing emotions without excess, avoiding home stress. A recent Illinois study found that insecure parents are more likely to suppress their emotions which can trigger intense emotional outbursts. These parents tend to give in to children’s demands for unhealthy snacks in response to distress or bad moods, and they permit increased television viewing. Both are associated with weight gain. On the other hand, a secure home more likely has four or more family meals a week, associated with increased consumption of fruits and vegetables, and less high-calorie foods, all reducing the risk of childhood obesity.

Michigan and Massachusetts. This study continues to fuel the “obesity paradox” – that lower household incomes have more obese children. More than 100,000 families represented, the study found that poorer economic status was associated with children watching more television, having less exercise, and eating more fast food and less fruits and vegetables.

Omaha. Starting when Omaha only had a half mile of bike lanes, Healthy Kids, Health Communities fostered the development of now 30 miles of bike lanes, bike racks on busses, an urban pocket park for mountain biking, and increased community gardens. Attention has been given to northeast and southeast neighborhoods where the aforementioned obesity paradox is alive and well. There, farmers’ markets brought healthy eating options, and the state’s first USDA-funded WIC Farmer’s Market coupon program served 3,300 families.

Lincoln. Teach a Kid to Fish is a public health initiative in Lincoln which promotes the message of 54321Go!, referring to the goal of 5 servings of fruits and vegetables a day, 4 glasses of water a day, 3 servings of low-fat dairy a day, 2 hours or less of screen time, and 1 hour or more of physical activity each day.

Through world-class research and patient care, UNMC generates breakthroughs that make life better for people throughout Nebraska and beyond. Its education programs train more health professionals than any other institution in the state. Learn more at unmc.edu and follow us on social media.

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A study by UNMC and Roswell Park Cancer Institute shows that a combination treatment strategy may provide a new option for patients with recurrent ovarian cancer.

The study, published in Cancer Immunology Research, found clinical benefit for women who were treated with the drug decitabine prior to administration of chemotherapy and a cancer vaccine.

“We’re encouraged by the results from the phase I clinical study and look forward to extending this concept to the phase II setting, where treatment efficacy is the principal end point,” said Adam Karpf, Ph.D., associate professor, Eppley Institute, and member, Fred & Pamela Buffett Cancer Center, at UNMC.

A prerequisite for the immune system to recognize and attack a tumor is the presence of high levels of a protein not normally found in healthy cells. Proteins with this profile are called tumor antigens and can be good targets for anticancer vaccines.

Phase II

Dr. Karpf’s co-principal investigator was Kunle Odunsi, M.D., Ph.D., professor and chair of the department of gynecologic oncology and director of the Center for Immunotherapy at Roswell Park Cancer Institute, Buffalo, N.Y.

Based on the encouraging findings of the Phase I trial, the investigators are planning a Phase II trial at UNMC and Roswell Park to specifically evaluate the clinical efficacy of this novel chemo-immunotherapy approach in patients with recurrent ovarian cancer.

For the original study, see Cancer Immunology Research 2014; 2:37-49. The study was funded by the National Cancer Institute, the Ovarian Cancer Research Fund, the Roswell Park Alliance Foundation, a Cancer Vaccine Collaborative Grant, the Anna Maria Kellen Clinical Investigator Award, and Eisai Pharmaceuticals. Drs. Karpf and Odunsi have declared no conflicts of interest.

“Preclinical studies by our group have shown that a specific class of tumor antigens is regulated by DNA methylation,” Dr. Karpf said. “Based on this knowledge, we developed the new clinical regimen.”

The investigators conducted a phase I dose-escalation trial of the DNA methyltransferase inhibitor decitabine, recruiting 12 women with epithelial ovarian cancer who had not responded to multiple lines of chemotherapy, with an estimated progression-free survival time of three months. Patients received decitabine on day one, the chemotherapy drug doxorubicin on day eight, and the cancer vaccine on day 15.

The investigators established the best sequence of drug administration: decitabine was effective only when administered before chemotherapy; it was ineffective if given after chemotherapy; vaccine administration was the last step.

Of the 10 patients evaluated, five had stable disease for up to 7.8 months, and one had a partial response with disease remission that lasted 5.8 months.

The dose escalation data suggested that lower doses of decitabine are associated with improved clinical response using this regimen. The treatment was well tolerated, and adverse events included hematologic side effects that were clinically manageable.

One remarkable result was that the therapeutic regimen led to a phenomenon called “antigen spreading,” Dr. Karpf said. “Although we immunized against a single antigen, we found induction of immune responses against an additional three antigens. We believe this may have resulted from the decitabine treatment.”